Sex differences in adipose tissue lipolysis and pathological cardiac hypertrophy

脂肪组织脂肪分解增强，循环中游离脂肪酸(FFA)升高，FA组成变化发生在肾上腺素旺盛的情况下，如运动，以及在心肌肥厚和慢性心力衰竭的发展过程中。相反，在从病理性心肌肥厚发展到终末期心力衰竭的过程中，心脏脂肪酸氧化速率降低，表明循环底物和局部心脏代谢不匹配。FFAs的增加和FAs组成的变化与心肌肥厚的发病和进展的相关性大多尚不清楚。雌性小鼠受到保护，免受病理性肥大/心力衰竭的影响。同时，女性表现出增强的肾上腺素能脂解作用。肾上腺素能脂肪组织脂肪分解的性别差异与心脏能量底物代谢的性别二型性相关，可能是雌性小鼠对病理刺激的肥大反应减弱的原因。基于我们在第一个资助期的研究结果，我们的目标是通过研究脂肪分解和病理性心肌肥厚的性别差异来表征增强型肾上腺素能脂肪组织脂肪分解在病理性心肌肥厚进展中的作用。为此，雌性/雄性脂肪特异性ATGL(脂肪甘油三酯脂肪酶)缺陷小鼠(aP2CRE-ATGL-FLOX)和野生型窝仔将受到横状主动脉缩窄(TAC)的攻击，以诱导心肌肥厚和随后的心力衰竭。随后将对小鼠进行心脏和代谢表型分析。为了进一步阐明心脏FA代谢的性别差异的分子机制，我们将分析脂肪酸摄取/氧化的关键分子以及心脏对特定FA的反应。

Augmented adipose tissue lipolysis, elevation of circulating free fatty acids (FFA), and changes in FA composition occurs in hyperadrenergic situations such as exercise, and during the development of cardiac hypertrophy and chronic heart failure. In contrary, during the progression from pathological cardiac hypertrophy to end-stage heart failure, the rate of cardiac fatty acid oxidation is reduced indicating a mismatch between circulating substrate and local cardiac metabolism. The relevance of increased FFAs and changes in FAcomposition for the pathogenesis and progression of cardiac hypertrophy is mostly unknown. Female mice are protected against pathological hypertrophy/ heart failure. In parallel, females exhibit enhanced adrenergic lipolysis. Sex-differences in adrenergic adipose tissue lipolysis associated with sexual dimorphisms in cardiac energy substrate metabolism may contribute to the diminished hypertrophic responses in female mice to pathological stimuli. Based on our results from the first funding period, we aim to characterize the role of augmented adrenergic adipose tissue lipolysis in the progression of pathological cardiac hypertrophy by studying sex-differences in lipolysis and pathological myocardial hypertrophy. For this, female/ male adipose-specific ATGL (adipose triglyceride lipase)-deficient mice (aP2 Cre –ATGL-flox) and wild-type littermates will be challenged with transverse aortic constriction (TAC) to induce cardiac hypertrophy and subsequent heart failure. Mice will be followed by cardiac and metabolic phenotyping. To further delineate the molecular mechanisms of sex-specifc differences in cardiac FA metabolism, we will analyze key molecules of fatty acid uptake/ oxidation and cardiac responses to selected FAs.